Pyrrolo(1,2-c)imidazole-1-one derivatives

ABSTRACT

Pyrrolo(1,2-c)imidazole derivatives of the formula   WHEREIN R is a lower alkyl, a phenyl or a benzyl radical, R1 is hydrogen, a lower alkyl or a phenyl radical and R2 is hydrogen or a lower alkyl radical. The compounds have C.N.S. activity.

@United States Patent Fontanella et al.

[ Aug. 26, I975 PYRROLOl 1,2-C llMlDAZOLE-I-ONE DERIVATIVES LuigiFontanella, Milan; Emilio Occelli, Parabiago, both of Italy Assignee:Gruppo Lepetit S.p.A., Milan, Italy Filed: Oct. 26, I973 Appl. No.:409,985

Inventors:

Foreign Application Priority Data References Cited FOREIGN PATENTS ORAPPLICATIONS ll/l97l Japan 260/309] Primary Exhminer-Ethel G. LoveAuomey, Agem, or Firm-Theodore Post; C. Kenneth Bjork ABSTRACT Pyrrolo[l,2-c )imidazole derivatives of the formula COOR R wherein R is a loweralkyl, a phenyl or a benzyl radical, R, is hydrogen, a lower alkyl or aphenyl radical and R, is hydrogen or a lower alkyl radical. Thecompounds have C.N.S. activity.

6 Claims, No Drawings PYRROLOI1,2-ClIMIDAZOLE-l-ONE DERIVATIVES SUMMARYOF THE INVENTION The present invention relates to pharmacologicallyactive pyrrolol l ,2-clirnidazole derivatives represented by formula (I)wherein R represents a lower alkyl, a phenyl or a benzyl radical, R,represents hydrogen, a lower alkyl or a phenyl radical and R representshydrogen or a lower alkyl radical.

In the specification and claims the terms lower alkyl and lower alkoxy"designate alkyl and alkoxy groups respectively, containing from I to 4carbon atoms; the terms a phenyl" and a benzyl designate phenyl andbenzyl groups, respectively. which may be substituted by one or twolower alkoxy groups.

DESCRIPTION OF THE PREFERRED EMBODIMENTS The compounds of the presentinvention are prepared by contacting a 2,5-disubstituted pyrrolidinerepresented by formula (II) CONHR COOR wherein R and R have thesignificance given before, with at least an equimolecular amount of analdehyde represented by the formula R CHO in which R, has the meaninggiven before, in an anhydrous inert or ganic solvent advantageouslyselected from the lower halogenated hydrocarbons, xylene,tetrahydrofuran and the like. in the presence of an acidic catalyst,such as, for example, para-toluenesulfonic acid. The reaction is carriedout by heating the reaction mixture, preferably at the boilingtemperature of the solvent, for a period of time ranging from about 3 to7 hours. The reaction product is then recovered and purified followingusual procedures in organic preparative chemistry, e.g., the crudecompound may be freed from any undesired by-product by columnchromatography and further purified by crystallization or distillationunder reduced pressure, depending on whether the compound is a solid oran oily substance.

The following additional description and examples further describe theinvention and the manner and pro cess of making and using it to enablethe art skilled to make and use the same and set forth the best modecontemplated by the inventors of carrying out the invention. r

EXAMPLE 1 2- Benzyl-S-carbethoxy-3-propyl-hexahydro- 1H- pyrrolo[ l,2-c]imidazole- I -one A mixture of 5 g. (0.0I8l mole) of 2-benzylcarbamyl-S-carbethoxypyrrolidine, 2.3 g. (0.032 mole) ofbutyraldehyde and 0.6 g. (0.0035 mole) of p-toluenesulfonic acid, in ml.of anhydrous xylene was refluxed for 5 hours in a Markusson apparatus.After cooling, the reaction mixture was washed twice with dilute aqueoussodium hydrogen carbonate. The organic layer was then dried over sodiumsulfate and the solvent was distilled off in vacuo. The residue obtainedwas chrmatographed through silica-gel using benzene containing 5% ofacetone as the eluent. Fractions of 100 ml. were collected. From thefractions 7 through 10, a product was obtained which was distilled underreduced pressure to give 3.8 g. of the pure titular compound, b.p.l187C./0.4 mm Hg.

EXAMPLES 2-1 1 The following compounds were prepared pursuant to theprocedure described in the previous example:

2. 5-Carbethoxy-2-(p-methoxyphenyl)-3-phenylhexahydro- 1H-pyrr0lo[ l,2-c1imidazolene- 1 -one from5-carbethoxy-2-(p-methoxyphenyl)carbamylpyrrolidine and benzaldehyde,yield 69.3%, m.p. l l5l I6C. (from diethyl ether).

3. S-Carbethoxy-3-(3,4-dimethoxyphenyl)-2 (pmethoxyphenyl )-hexahydrolH-pyrr0lo[ l .2- climidazolene-l-one from 5 carbethoxy-2(pmethoxyphenyl)carbamylpyrrolidine and 3,4-dimethoxybenzaldehyde, yield67.9%, b.p. 250C./0.4 mm Hg.

4. 5Carbethoxy-2-( p-methoxyphenyl )-3-propylhexahydrol H-pyrrolo[ l,2-cIimidazolenel-one, from 5 carbethoxy-2-( p-methoxyphenyl)carbamylpyrrolidine and butyraldehyde, yield 71.8%, b.p. lC./0.4 mm Hg.

5. 5-Carbethoxy-2-phenyl-hexahydrol Hpyrrolol l,2-cIimidiazolene-l-onefrom 5 carbethoXy-2- phenylcarbamylpyrrolidinc and formaldehyde, yield42%, b.p. l98200C./O.4 mm Hg.

6. 2-Benzyl-5-carbethoxy-3-phenyl-hexahydrol H- pyrrolo-[ l,2-climidazolene- I -one from 2- benzylcarbamyl-S-carbethoxy-pyrrolidineand benzaldehyde, yield 23.8%, m.p. 5657C. (from ethanol/- diethylether).

7. 2-Benzyl-5-carbethoxy-3-(3,4-dimethoxyphenyl)- hexahydrol H-pyrrolo[l,2-c ]imidazolene-l-one from Z-benzylcarbamyl-5-carbethoxypyrrolidineand 3,4-dimethoxybenzaldehyde, yield 68%, b.p. 238240C./0.4 mm Hg.

8 and 9. 5-Carbethoxy-2-methyl3-propylhexahydrol H-pyrrolol l ,2-c]imidazolene- I 'one a-isomer and5-carbethoxy2methyl-3-propyl-hexahydrolH-pyrrolo[ l,2-climidazolene-l-one B-isomer were prepared as a mixture of the twoisomers starting from 5-carbethoxy-2-(methylcarbamyl)pyrrolidine andbutyraldehyde. They were separated by column chromatography andcharacterized by NMR techniques.

l0. 5-Carbethoxy 2-methyl-3-phenyl-hexahydrol H- pyrrolo-[l,2-climidazolene-l-one from 5carbethoxy- 2-methylcarbamyl-pyrrolidineand benzaldehyde, yield 50%, b.p. l73l75C./0.5 mm Hg.

l l. 5-Carbethoxy-3-( 3,4-dimethoxyphenyl )-2- methyl-hexahydrolH-pyrrolo[ l,2-c limidazolenel-one fromS-carbethoxy-2-(methylcarbamyl)pyrrolidine and3,4-dimethoxybenzaldehyde. yield 72.4%. b.p. 2l0C./0,4 mm Hg.

Pursuant to the methods described by Cignarella and Nathansohn inJournal Organic Chemistry 26, 1500, 1961, and by Cignarella and Testa inGazzetta Chimica ltaliana, 92, I093, 1962, the following representativestarting compounds of formula (ll) were prepared, generally as a mixtureof the two cisand trans-isomers:

two possible isomers. In this case, the end compounds of formula (I)will be a mixture of the two possible isomers, aand 5-. which may beseparated with the aid of well known techniques. for example, by columnchromatography. It is to be noted, that even if the starting material asthe mixture of the two possible isomers is used. the formation of amixture of the aand B-compounds is not necessarily obtained. Owing tothe presence of several asymmetry centers, the compounds of formula (I)may also be mixtures of optical isomers: there can theoretically be fourisomers when R is hy- CONllCH t is obvious that the two isomers may beseparated and :haracteriyed as shown in the Examples, for the com-)ounds of formula (ll) wherein R is CH;,. Thus, ii. as he startingmaterial, the cisor the trans-form of the :ompound of formula (H) isemployed. a product of 'ormula (I) will be obtained, which willhereinafter be ralled the ,B-isomer if it is derived from a pyrrolidineof ormula (ll) having the cis structure, or the a-isomcr if t is derivedfrom a pyrrolidine of formula (II) having he transstrueture. However. itis preferred to use as he starting materials for the subsequentcondensation tep with the aldehyde of formula (Ill) mixtures of the170l75C/O.3 mm Hg.

drogen as then two asymmetry centers are present at positions 5 and 8,or eight when R, is other than hydrogen, since in this case there arethen three asymmetry centers at positions 3, 5 and 8. It is thereforeobvious that the final products may be separated into the possible pairsof enantiomers.

The compounds of the invention have central nervous system (C.N.S,)activity. This activity was evaluated by investigating the behavior oimice and rats after administering an effective dose of one of thecompounds. A decrease of the spontaneous activity in mice was taken as ameasure of the sedative effect. while an 3.90l,9ll

amounts of about 50 mg/kg i.p. of representative compounds of Examples2. 5, 7, 8 and 10 were found to be active on the above mentionedparameters.

The favorable biological properties are coupled with a very lowtoxicity, since the LD,-, values are always higher than 1000 mg/kg i.p.in mice What is claimed is:

l. A compound represented by the formula I 7 RH R COOR l wherein R isselected from the group consisting of a lower alkyl, a phenyl and abenzyl radical, R, is selected from the group consisting of hydrogen. alower alkyl and a phenyl radical, wherein the phenyl and benzyl radicalsof R and R may be substituted by one or two lower alkoxy groups, and Ris selected from the group consisting of a hydrogen atom and a loweralkyl radical.

2. The compound of claim 1 which is 5-carbethoxy-2-(p-methoxyphenyl)-3-phenyl-hexahydrol H- pyrrolo[ l,2-cl-imidazolene- I-one.

3. The compound of claim 1 which is S-carbethoxy-Z- phenyl-hexahydrolH-pyrrolol l,2-c]imidazolenel-one.

4. The compound of claim I which is 2-benzyl-5- carbethoxy-3-(3,4-dimethoxyphenyl )-hexahydrol H- pyrrolo[ 1,2-cl-imidazolene- I -one.

5. The compound of claim 1 which is 01-5-carbethoxy-Z-methyl-3-propyl-hexahydrol H-pyrrolo[ l ,2-climidazolene- I-one 6. The compound of claim I which is 5-carbethoxy-2-methyl-3-phenyl-hexahydro-1H-pyrrolo[ 1,2-

c imidazolene- I -one.

Page 1 of 2 UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OFCORRECTION et al.

PATENT NO. I 3 901, 91].

DATED I August 26, 1975 INVENTOR(S) I L. Fontanella,

It is certified that error appears in the ab0ve-identified patent andthat said Letters Patent are hereby corrected as shown below:

Column 2, line "chrmatographed" should read chromatographed--;

Column 2, line imidazole;

Column 2, line -imidazole--;

Column 2, line imidazole-;

Column 2, line -imidazole;

Column 2, line -imidazole;

Column 2, line imidazole-;

Column 2, line -imidazole;

Column 2, line --imidazole;

"imidazolene" should read "imidazolene" should read "imidazolene" shouldread "imidiazolene" should read "imidazolene" should read "imidazolene"should read "imidazolene" should read "imidazolene" should read"isomers" should read -isomer;

"imidazolene" should read page 2 of 2 UNITED STATES PATENT AND TRADEMARKOFFICE CERTIFICATE OF CORRECTION PATENT NO. 3,901,911 DATED August 26,

|NVENTOR(S) I L. Fontanella, et al.

It is certified that error appears in the above-identified patent andthat said Letters Patent are hereby corrected as shown below:

Column 3, line -imidazo1e-;

Column 6, line imidazole;

Column 6, line imidazole-;

Column 6, line imidazole-;

Column 6, line -imidazole;

Column 6, line -imidazole.

[SEAL] Attest:

"imidazolene" "imidazolene" "imidazolene" "imidazolene" "imidazolene""imidazolene" should read should read should read should read shouldread should read RUTH C. MASON A Nesting Officer second Day of March1976C. MARSHALL DANN Commissioner oflarenrs and Trademarks

1. A COMPOUND REPRESENTED BY THE FORMULA
 2. The compound of claim 1which is5-carbethoxy-2-(p-methoxyphenyl)-3-phenyl-hexahydro-1H-pyrrolo(1,2-c)-imidazolene-1-one.
 3. The compound of claim 1 which is5-carbethoxy-2-phenyl-hexahydro-1H-pyrrolo(1,2-c)imidazolene-1-one. 4.The compound of claim 1 which is 2-benzyl-5-carbethoxy-3-(3,4-dimethoxyphenyl)-hexahydro-1H-pyrrolo(1,2-c)-imidazolene-1-one.
 5. Thecompound of claim 1 which is Alpha-5-carbethoxy-2-methyl-3-propyl-hexahydro-1H-pyrrolo(1,2-c)imidazolene-1-one.
 6. The compound of claim 1 which is5-carbethoxy-2-methyl-3-phenyl-hexahydro-1H-pyrrolo(1,2-c)imidazolene-1-one.